DESCRIPTION: The bacteria colonizing the tissues of the mouth exist as compositionally and structurally complex populations in biofilms. In most cases, oral biofilms are compatible with health. It is perturbations in the environment that result in changes in the composition and metabolic activities of bacterial biofilms - driving the initiation and progression of oral diseases. Among the environmental stresses that have been established to have a major impact on the expression of virulence genes of oral bacteria, and on the pathogenic potential of oral biofilms, are low pH, nutrient limitation and oxygen. Conditions in the oral cavity change rapidly and bacteria are forced to respond efficiently to fluctuations in environmental conditions and to tolerate and adapt to environmental stresses. Unfortunately for their host, oral pathogens appear to have evolved elegant and complex mechanisms to cope with environmental stress to gain a selective advantage when the normal homeostatic mechanisms'of oral biofilms are perturbed. Acquiring a thorough understanding of the molecular mechanisms of biofilm formation and stress tolerance by oral pathogens is a necessary first step toward the development of novel and broadly effective strategies to combat oral diseases. The overall goals of this application are to provide detailed molecular and physiologic information about the capacity of oral bacteria to form and persist in biofilms, with a particular focus on environmental stresses that can modulate the virulence of oral bacteria and enhance the pathogenic potential of oral biofilms. To accomplish these goals, the following Specific Aims have been established: Aim 1. Investigation of molecular control of the stress regulon of Streptococcus mutans, with particular focus on genetic response circuits for biofilm formation, nutrient limitation and acid tolerance. Aim 2. Comparisons of the transcriptomes of five regulatory mutants followed by a functional genomic analysis of the role in biofilm formation and stress tolerance of genes that are aberrantly regulated in these mutants.